The invention relates to a nutritional or dietetic composition or supplement.
Fatty acid oxidation plays a major role in the production of energy, and is essential during periods of fasting. Serious disorders in fatty acid metabolism can arise which range from skeletal and/or cardiac muscle weakness to episodes of metabolic apnea to death resembling sudden infant death syndrome. These disorders manifest with severe cardiomyopathy, hypoglycemia, myopathy, microvesicular fat deposition in affected organs, and/or fulminant hepatic failure. Patients suffering from inborn genetic errors in fatty acid metabolism often experience fatal or repeated severely debilitating episodes upon failure to generate energy via fatty acid metabolism. Premature infants require a maintenance of a high blood sugar level. Often, their routine diet does not provide sufficient amounts of carbohydrate energy sources and their fat metabolism enzymes are not efficient at birth. Elderly patients also experience difficulty in the regulation of blood sugar levels due to a decreased appetite and inefficient metabolism.
Saturated fatty acids are represented by the following structure: 
where R represents an alkyl group. Naturally occurring fatty acids derived from higher plant and animal lipids include both saturated and unsaturated even-numbered carbon chains. The most abundant naturally occurring saturated fatty acids are palmitic acid (16 carbons; C16) and stearic acid (18 carbons; C18). Shorter-chain fatty acids (12-14 carbons; C12 to C14) and longer-chain fatty acids (up to 28 carbons; C28) naturally occur in small quantities. Fatty acids of less than 10 carbons are rarely present in animal lipids, with the exception of milk fat comprising about 32% oleic acid (unsaturated C18), about 15% palmitic acid (C16), about 20% myristic acid (C14), about 15% stearic acid (C18), about 6% lauric acid (C12), and about 10% fatty acids of 4-10 carbons (C4-C10).
Fatty acids are generally categorized by the length of the carbon chain attached to the carboxyl group: short-chain for 4 to 6 carbons (C4-C6), medium-chain for 8 to 14 carbons (C8-C14), long-chain for 16 to 18 carbons (C16-C18), and very long-chains for 20 to 28 carbons (C20-C28).
The process by which fatty acids are metabolized involves mitochondrial xcex2-oxidation in the mitochondria of the cell. As illustrated in FIG. 1, fatty acid oxidation of a long-chain fatty acid such as palmitic acid begins transport of the fatty acid through the plasma membrane via a plasma membrane carnitine transporter. As the fatty acid passes through the outer mitochondrial membrane, the fatty acid is converted in the presence of Coenzyme A (CoASH) and acyl-CoA synthetase into a fatty acid ester of Coenzyme A (fatty acyl-CoA) at the expense of ATP. The fatty acyl-CoA is converted into fatty acylcarnitine in the presence of carnitine and carnitine palmitoyltransferase I (CPT I). The fatty acylcarnitine then passes the inner membrane of the mitochondria, a step which is catalyzed by the carnitine/acylcarnitine translocase enzyme. Once inside the mitochondria, the fatty acylcarnitine is then converted back into fatty acyl-CoA in the presence of carnitine palmitoyltransferase II (CPT II). In the oxidation cycle within the mitochondria, the fatty acyl-CoA is dehydrogenated by removal of a pair of hydrogen atoms from the xcex1 and xcex2 carbon atoms via a chain-specific acyl-CoA dehydrogenase to yield the xcex1,xcex2-unsaturated acyl-CoA, or 2-trans-enoyl-CoA. The appropriate acyl-CoA dehydrogenase is determined by the carbon chain length of the fatty acyl-CoA, i.e., long-chain acyl-CoA dehydrogenase (LCAD; C12 to C18), medium-chain acyl-CoA dehydrogenase (MCAD; C4 to C12), short-chain acyl-CoA dehydrogenase (SCAD; C4 to C6), or very long-chain acyl-CoA dehydrogenase (VLCAD; C14 to C20). The xcex1,xcex2-unsaturated acyl-CoA is then enzymatically hydrated via 2-enoyl-CoA hydratase to form L-3-hydroxyacyl-CoA, which in turn is dehydrogenated in an AND-linked reaction catalyzed by a chain-specific L-3-hydroxyacyl-CoA dehydrogenase to form xcex2-ketoacyl-CoA. The appropriate L-3-hydroxyacyl-CoA dehydrogenase is determined by the carbon chain length of the L-3-hydroxyacyl-CoA, i.e., long-chain L-3-hydroxyacyl-CoA dehydrogenase(LCHAD; C12 to C18) or short-chain L-3-hydroxyacyl-CoA dehydrogenase(SCHAD; C4 to C16 with decreasing activity with increasing chain length). The xcex2-ketoacyl CoA ester undergoes enzymatic cleavage by attack of the thiol group of a second molecule of CoA in the presence of 3-ketoacyl-CoA thiolase, to form fatty acyl-CoA and acetyl-CoA derived from the xcex1 carboxyl and the xcex2 carbon atoms of the original fatty acid chain. The other product, a long-chain saturated fatty acyl-CoA having two fewer carbon atoms than the starting fatty acid, now becomes the substrate for another round of reactions, beginning with the first dehydrogenation step, until a second two-carbon fragment is removed as acetyl-CoA. At each passage through this spiral process, the fatty acid chain loses a two-carbon fragment as acetyl-CoA and two pairs of hydrogen atoms to specific acceptors.
Each step of the fatty acid oxidation process is catalyzed by enzymes with overlapping carbon chain-length specificities. Inherited disorders of fatty acid oxidation have been identified in association with the loss of catalytic action by these enzymes. These include defects of plasma membrane carnitine transport; CPT I and II; carnitine/acylcarnitine translocase; very-long-chain, medium-chain, and short-chain acyl-CoA dehydrogenases (i.e., VLCAD, MCAD, and SCAD, respectively); 2,4-dienoyl-CoA reductase; long-chain 3-hydroxyacyl-CoA dehydrogenase acyl-CoA (LCHAD), and mitochondrial trifunctional protein (MTP) deficiency. To date, treatment for medium chain dehydrogenase (MCAD) deficiency has been found. However, the remaining defects often are fatal to patients within the first year of life, and no known effective treatment has been made available. In particular, patients suffering from severe carnitine/acylcarnitine translocase deficiency routinely die, there are no known survivors, and no known treatment has been found.
Attempts to treat these disorders have centered around providing food sources which circumvent the loss of catalytic action by the defective enzyme. For example, the long-chain fatty acid metabolic deficiency caused by a defective carnitine/acylcarnitine translocase enzyme (referred hereinafter as xe2x80x9ctranslocase deficiencyxe2x80x9d) often leads to death in the neonatal period. Providing carnitine, a high carbohydrate diet, and medium-chain triglycerides to one translocase-deficient patient failed to overcome the fatty acid metabolic deficiency. It was believed that the metabolism of medium-chain fatty acids would not require the carnitine/acylcarnitine translocase enzyme, since medium-chain fatty acids are expected to freely enter the mitochondria. Thus, infant formulas were developed comprising even-carbon number medium-chain triglycerides (MCT) (e.g., 84% C8, 8% C6 and 8% C10) which were expected to by-pass the translocase defect. Fatalities continue to occur despite treatment attempts with these formulas.
With the exception of pelargonic acid (saturated fatty acid with 9 carbons; C9), odd-carbon number fatty acids are rare in higher plant and animal lipids. Certain synthetic odd-carbon number triglycerides have been tested for use in food products as potential fatty acid sources and in the manufacture of food products. The oxidation rates of odd-chain fatty acids from C7 and C9 triglycerides have been examined in vitro in isolated piglet hepatocytes. (Odle, et al. 1991. xe2x80x9ctilization of medium-chain triglycerides by neonatal piglets: chain length of even- and odd-carbon fatty acids and apparent digestion/absorption and hepatic metabolism,xe2x80x9d J Nutr 121:605-614; Lin, X, et al. 1996. xe2x80x9cAcetate represents a major product of heptanoate and octanoate beta-oxidation in hepatocytes isolated from neonatal piglets,xe2x80x9d Biochem J 318:235-240; and Odle, J. 1997. xe2x80x9cNew insights into the utilization of medium-chain triglycerides by the neonate: observations from a piglet model,xe2x80x9d J Nutr 127:1061-1067). The importance of odd-chain fatty acids propionate (C3), valerate (C5), and nonanoate (C9) as gluconeogenic precursors was evaluated in hepatocytes from starved rats. (Sugden, et al. 1984. xe2x80x9cOdd-carbon fatty acid metabolism in hepatocytes from starved rats,xe2x80x9d Biochem Int""l 8:61-67). The oxidation of radiolabeled margarate (C17) was examined in rat liver slices. (Boyer, et al. 1970. xe2x80x9cHepatic metabolism of 1-14C octanoic and 1-14C margaric acids,xe2x80x9d Lipids 4:615-617).
In vivo studies utilizing C3, C5, C7, C9, C11, and C17 have also been carried out in vivo in guinea pigs, rabbits, and rats. In vivo oxidation rates of systematically infused medium-chain fatty acids from C7 and C9 triglycerides and a C7/C9 triglyceride mixture have been examined in neonatal pigs. (Odle, et al. 1992. xe2x80x9cEvaluation of [1-14C]-medium-chain fatty acid oxidation by neonatal piglets using continuous-infusion radiotracer kinetic methodology,xe2x80x9d J Nutr 122:2183-2189; and Odle, et al. 1989. xe2x80x9cUtilization of medium-chain triglycerides by neonatal piglets: II. Effects of even- and odd-chain triglyceride consumption over the first 2 days of life on blood metabolites and urinary nitrogen excretion,xe2x80x9d J Anima Sci 67:3340-3351). Rats fed triundecanoin (saturated C11) were observed to maintain nonfasting blood glucose levels during prolonged fasting. (Anderson, et al. 1975. xe2x80x9cGlucogenic and ketogenic capacities of lard, safflower oil, and triundecanoin in fasting rats,xe2x80x9d J Nutr 105:185-189.) An emulsion of trinonanoin (C9) and long-chain triglycerides was infused into rabbits for evaluation as long-term total parenteral nutrition. (Linseisen, et al. 1993. xe2x80x9cOdd-numbered medium-chain triglycerides (trinonanoin) in total parenteral nutrition: effects on parameters of fat metabolism in rabbits,xe2x80x9d J Parenteral and Enteral Nutr 17:522-528). The triglyceride triheptanoin containing the saturated 7-carbon fatty n-heptanoic acid (C7) has also been reportedly used in Europe in agricultural feed, as a tracer molecule in the manufacture of butter, and as a releasing agent in the manufacture of chocolates and other confectioneries. However, there has been no indication heretofore that a seven-carbon fatty acid is safe for consumption by humans or has any particular nutritional benefit to humans.
It has now been found that acquired metabolic derangements and inherited metabolic disorders, especially fatty acid metabolic defects, can be overcome using a nutritional composition comprising a seven-carbon fatty acid (C7) such as n-heptanoic acid. Patients experiencing defective or reduced fatty acid metabolism can be treated with a nutritional composition comprising a seven-carbon fatty acid such as n-heptanoic acid and/or its triglyceride triheptanoin as a very efficient energy source. Patients needing rapid energy may also benefit from consumption of the seven-carbon fatty acid or its triglyceride.
In one aspect, the present invention is a nutritional supplement comprising a saturated seven-carbon fatty acid. A seven-carbon fatty acid useful in the present invention is n-heptanoic acid. The seven-carbon fatty acid can be provided in the form of a triglyceride, preferably comprising n-heptanoic acid. The triglyceride triheptanoin at a concentration sufficient to provide a beneficial effect is most useful in this aspect of the present invention. Preferably, the seven-carbon fatty acid is at a concentration to provide at least about 25% of the total dietary calories.
In yet another aspect, the invention is a pharmaceutical preparation which comprises a seven-carbon fatty acid. A seven-carbon fatty acid useful in the present invention is n-heptanoic acid. The seven-carbon fatty acid can be provided in the form of a triglyceride, preferably comprising n-heptanoic acid. The triglyceride triheptanoin at a concentration sufficient to provide a beneficial effect is most useful in this aspect of the present invention. The pharmaceutical preparation can be administered orally or parenterally.
In yet another aspect, the invention is a pharmaceutical preparation in dosage unit form adapted for administration to provide a therapeutic effect in a patient having at least one metabolic disorder, wherein the pharmaceutical preparation comprises a seven-carbon fatty acid. The metabolic disorder can result from a fatty acid metabolic defect, for example, carnitine palmitoyltransferase I, carnitine palmitoyltransferase II, carnitine/acylcarnitine translocase, cardiac form of very-long-chain acyl-CoA dehydrogenase, hypoglycemic form of very-long-chain acyl-CoA dehydrogenase, muscle form of very-long-chain acyl-CoA dehydrogenase, mitochondrial trifunctional protein, long-chain L-3-hydroxy-acyl-CoA dehydrogenase, and short-chain acyl-CoA dehydrogenase. A seven-carbon fatty acid useful in the present invention is n-heptanoic acid. The seven-carbon fatty acid can be provided in the form of a triglyceride, preferably comprising n-heptanoic acid. The triglyceride triheptanoin at a concentration sufficient to provide a beneficial effect is most useful in this aspect of the present invention. The pharmaceutical preparation can be administered orally or parenterally.
In yet another aspect, the invention is a pharmaceutical unit dosage form which comprises a seven-carbon fatty acid and a pharmacologically acceptable carrier, wherein the dosage form is provided in an amount effective to enhance the fatty acid metabolism of a patient having at least one metabolic disorder. The metabolic disorder can result from a fatty acid metabolic defect, for example, carnitine palmitoyltransferase I, carnitine palmitoyltransferase II, carnitine/acylcarnitine translocase, cardiac form of very-long-chain acyl-CoA dehydrogenase, hypoglycemic form of very-long-chain acyl-CoA dehydrogenase, muscle form of very-long-chain acyl-CoA dehydrogenase, mitochondrial trifunctional protein, long- chain L-3-hydroxy-acyl-CoA dehydrogenase, and short-chain acyl-CoA dehydrogenase. A seven-carbon fatty acid useful in the present invention is n-heptanoic acid. The seven-carbon fatty acid can be provided in the form of a triglyceride, preferably comprising n-heptanoic acid. The triglyceride triheptanoin at a concentration sufficient to provide a beneficial effect is most useful in this aspect of the present invention. The pharmaceutical dosage unit form can be administered orally or parenterally.
In another aspect, the invention is the use of a nutritional supplement comprising a seven-carbon fatty acid to enhance fatty acid metabolism in humans. A seven-carbon fatty acid useful in the present invention is n-heptanoic acid. The seven-carbon fatty acid can be provided in the form of a triglyceride, preferably comprising n-heptanoic acid. The triglyceride triheptanoin at a concentration sufficient to provide a beneficial effect is most useful in this aspect of the present invention. Preferably, the seven-carbon fatty acid provides at least about 25% of the total calories of the supplement.
In another aspect, the invention is the use of a nutritional supplement comprising a seven-carbon fatty acid as a nutritional source of glucose. A seven-carbon fatty acid useful in the present invention is n-heptanoic acid. The seven-carbon fatty acid can be provided in the form of a triglyceride, preferably comprising n-heptanoic acid. The triglyceride triheptanoin at a concentration sufficient to provide a beneficial effect is most useful in this aspect of the present invention. Preferably, the seven-carbon fatty acid provides at least about 25% of the total calories of the supplement.
In another aspect, the invention is the use of a pharmaceutical preparation in dosage unit form to provide a therapeutic effect in a patient having at least one metabolic disorder, wherein the pharmaceutical preparation comprises a seven-carbon fatty acid. The metabolic disorder can result from a fatty acid metabolic defect, for example, carnitine palmitoyltransferase I, carnitine palmitoyltransferase II, carnitine/acylcarnitine translocase, cardiac form of very-long-chain acyl-CoA dehydrogenase, hypoglycemic form of very-long-chain acyl-CoA dehydrogenase, muscle form of very-long-chain acyl-CoA dehydrogenase, mitochondrial trifunctional protein, long-chain L-3-hydroxy-acyl-CoA dehydrogenase, and short-chain acyl-CoA dehydrogenase. A seven-carbon fatty acid useful in the present invention is n-heptanoic acid. The seven-carbon fatty acid can be provided in the form of a triglyceride, preferably comprising n-heptanoic acid. The triglyceride triheptanoin at a concentration sufficient to provide a beneficial effect is most useful in this aspect of the present invention. Preferably, the seven-carbon fatty acid provides at least about 25% of the total calories of the supplement.
In yet another aspect, the invention is a method of providing enhanced energy potential per gram of food substance which comprises adding a seven-carbon fatty acid to the food substance. A seven-carbon fatty acid useful in the present invention is n-heptanoic acid. The seven-carbon fatty acid can be provided in the form of a triglyceride, preferably comprising n-heptanoic acid. The triglyceride triheptanoin at a concentration sufficient to provide a beneficial effect is most useful in this aspect of the present invention. Preferably, the food substance is administered orally or parenterally.
In another aspect, the invention is a method of treating a patient having at least one metabolic disorder with a nutritional supplement comprising a seven-carbon fatty acid. The metabolic disorder can result from a fatty acid metabolic defect, for example, carnitine palmitoyltransferase I, carnitine palmitoyltransferase II, carnitine/acylcarnitine translocase, cardiac form of very-long-chain acyl-CoA dehydrogenase, hypoglycemic form of very-long-chain acyl-CoA dehydrogenase, muscle form of very-long-chain acyl-CoA dehydrogenase, mitochondrial trifunctional protein, long-chain L-3-hydroxy-acyl-CoA dehydrogenase, and short-chain acyl-CoA dehydrogenase. A seven-carbon fatty acid useful in the present invention is n-heptanoic acid. The seven-carbon fatty acid can be provided in the form of a triglyceride, preferably comprising n-heptanoic acid. The triglyceride triheptanoin at a concentration sufficient to provide a therapeutic effect is most useful in this aspect of the invention. Preferably, the seven-carbon fatty acid is added at a concentration to provide at least about 25% of the total dietary calories.
In yet another aspect, the invention is a method for increasing the efficiency of fatty acid metabolism by administering to a patient a nutritional supplement comprising a seven-carbon fatty acid. A seven-carbon fatty acid useful in the present invention is n-heptanoic acid. The seven-carbon fatty acid can be provided in the form of a triglyceride, preferably comprising n-heptanoic acid. The triglyceride triheptanoin at a concentration sufficient to provide a therapeutic effect is most useful in this aspect of the present invention. Preferably, the seven-carbon fatty acid is added at a concentration to provide at least about 25% of the total dietary calories.